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Disruption of the Rb-Raf-1 Interaction Inhibits Tumor Growth and Angiogenesis

Piyali Dasgupta,¹ Jiazhi Sun,^1, Sheng Wang,^1, Gina Fusaro,¹ Vicki Betts,^1, Jaya Padmanabhan,² Saïd M. Sebti,¹ and Srikumar P. Chellappan^1*

Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute,¹ Department of Biochemistry, University of South Florida, Tampa, Florida²

Received 3 March 2004/ Returned for modification 28 April 2004/ Accepted 2 August 2004

The retinoblastoma tumor suppressor protein (Rb) plays a vital role in regulating mammalian cell cycle progression and inactivation of Rb is necessary for entry into S phase. Rb is inactivated by phosphorylation upon growth factor stimulation of quiescent cells, facilitating the transition from G₁ phase to S phase. Although the signaling events after growth factor stimulation have been well characterized, it is not yet clear how these signals contact the cell cycle machinery. We had found previously that growth factor stimulation of quiescent cells lead to the direct binding of Raf-1 kinase to Rb, leading to its inactivation. Here we show that the Rb-Raf-1 interaction occurs prior to the activation of cyclin and/or cyclin-dependent kinases and facilitates normal cell cycle progression. Raf-1-mediated inactivation of Rb is independent of the mitogen-activated protein kinase cascade, as well as cyclin-dependent kinases. Binding of Raf-1 seemed to correlate with the dissociation of the chromatin remodeling protein Brg1 from Rb. Disruption of the Rb-Raf-1 interaction by a nine-amino-acid peptide inhibits Rb phosphorylation, cell proliferation, and vascular endothelial growth factor-mediated capillary tubule formation. Delivery of this peptide by a carrier molecule led to a 79% reduction in tumor volume and a 57% reduction in microvessel formation in nude mice. It appears that Raf-1 links mitogenic signaling to Rb and that disruption of this interaction could aid in controlling proliferative disorders.

Present address: Pennsylvania State University College of Medicine, Hershey, PA 17033-0850.

Present address: Cancer Research Center, Boston University School of Medicine, Boston, MA 02118.

Present address: Molecular Medicine Laboratories, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.

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